Correlating in Vitro Solubilization and Supersaturation Profiles with in Vivo Exposure for Lipid Based Formulations of the CETP Inhibitor CP-532,623.

Lipid based formulations (LBFs) are a promising formulation strategy for many poorly water-soluble drugs and have been shown previously to enhance the oral exposure of CP-532,623, an oral cholesteryl ester transfer protein inhibitor. In the current study, an in vitro lipid digestion model was used to probe the relationship between drug solubilization and supersaturation on in vitro dispersion and digestion of LBF containing long chain (LC) lipids and drug absorption in vivo. After in vitro digestion of LBF based on LC lipids, the proportion of CP-532,623 maintained in the solubilized state in the aqueous phase of the digest was highest in formulations containing Kolliphor RH 40, and in most cases outperformed equivalent formulations based on MC lipids. Subsequent administration of the LC-LBFs to beagle dogs resulted in reasonable correlation between concentrations of CP-532,623 measured in the aqueous phase of the in vitro digest after 30 min digestion and in vivo exposure (AUC); however, the LC-LBFs required greater in vitro drug solubilization to elicit similar in vivo exposure when compared to previous studies with MC-LBF. Although post digestion solubilization was enhanced in LC-LBF compared to MC-LBF, equilibrium solubility studies of CP-532,623 in the aqueous phase isolated from blank lipid digestion experiments revealed that equilibrium solubility was also higher, and therefore supersaturation lower. A revised correlation based on supersaturation in the digest aqueous phase and drug absorption was therefore generated. A single, linear correlation was evident for both LC- and MC-LBF containing Kolliphor RH 40, but this did not extend to formulations based on other surfactants. The data suggest that solubilization and supersaturation are significant drivers of drug absorption in vivo, and that across formulations with similar formulation composition good correlation is evident between in vitro and in vivo measures. However, across dissimilar formulations, solubilization and supersaturation alone are not sufficient to explain drug exposure and other factors also likely play a role.

In vitro-in vivo evaluation of lipid based formulations of the CETP inhibitors CP-529,414 (torcetrapib) and CP-532,623.

The present study investigated the use of lipid based drug delivery systems to enhance the oral bioavailability of the CETP inhibitors CP-532,623 and torcetrapib. A series of self-emulsifying lipid based drug delivery systems (SEDDS) were assembled and examined using an in vitro lipid digestion model to evaluate patterns of drug precipitation under simulated intestinal conditions. Drug exposure after oral administration of the same formulations was subsequently assessed in beagle dogs. CP-532,623 was maintained in a solubilised state during dispersion of most formulations in simulated intestinal fluid, however, solubilisation capacity was reduced to various degrees upon in vitro digestion. Administration of SEDDS formulations to beagle dogs resulted in moderate differences in plasma AUC when compared to the differences in solubilisation observed in vitro. Similar trends were observed for torcetrapib. In all cases, however, in vivo exposure of CP-532,623 was greatly enhanced by administration in lipid based drug delivery systems when compared to a powder formulation. Some correlation between in vitro solubilisation and in vivo drug exposure (AUC) was evident; however, this was not linear. The data suggest that for highly lipophilic drugs such as CP-532,623 in vitro digestion data may be a conservative in vitro indicator of utility and that good exposure may be evident even for formulations that result in significant drug precipitation during in vitro digestion.

Identification of a novel, non-tetrahydroquinoline variant of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib, with improved aqueous solubility.

1. Elaborate studies of cholesteryl ester transfer protein (CETP) polymorphisms and genetic deficiency in humans suggest direct links between CETP, high-density lipoprotein cholesterol (HDL-c) levels and coronary heart diseases. The hypothesis that CETP inhibition by small molecule inhibitors raises HDL-c has been validated clinically with structurally-diverse CETP inhibitors such as torcetrapib, anacetrapib, dalcetrapib and evacetrapib. 2. Despite promising phase 2 results with respect to HDL-c elevation, torcetrapib was discontinued in phase 3 trials due to increased mortality rates in the cardiovascular outcomes study. Emerging evidence for the adverse effects hints at off-target chemotype-specific cardiovascular toxicity, possibly related to the pressor effects of torcetrapib, since structurally diverse CETP inhibitors such as anacetrapib, evacetrapib and dalcetrapib are not associated with blood pressure increases in humans. Nonclinical follow-up studies showed that torcetrapib induces aldosterone biosynthesis and secretion in vivo and in vitro, an effect which is not observed with other CETP inhibitors in clinical development. 3. As part of ongoing efforts to identify novel CETP inhibitors devoid of pressor effects, strategies were implemented towards the design of compounds, which lack the 1,2,3,4-tetrahydroquinoline (THQ) scaffold present in torcetrapib. In this article, we disclose results of structure-activity relationship studies for a series of novel non-THQ CETP inhibitors, which resulted in the identification of a novel isonipecotic acid derivative 10 (also referred to as PF-04445597) with vastly improved oral pharmacokinetic properties mainly as a result of improved aqueous solubility. This feature is attractive in that, it bypasses significant investments needed to develop compatible solubilizing formulation(s) for oral drug delivery of highly lipophilic and poorly soluble compounds; attributes, which are usually associated with small molecule CETP inhibitors. PF-04445597 was also devoid of aldosterone secretion in human H295R adrenal carcinoma cells.